Abnormal liver lipid metabolism in adult offspring induced by prenatal ozone exposure.

The health impacts of ozone (O3) remain vastly underestimated, particularly regarding the transgenerational effects of prenatal O3 exposure on offspring hepatic lipid metabolism, which has rarely been investigated. This study established a dose-dependent prenatal O3 exposure mouse model (0, 0.5, and 1.0 ppm) combined with transcriptomic sequencing and lipidomic profiling to systematically evaluate hepatic metabolic dysregulation in adult offspring. Results revealed that high-dose O3 exposure significantly elevated hepatic total cholesterol (TC) levels in female offspring, with no analogous effects observed in males. Further multi-omics analysis demonstrated O3-induced remodeling of hepatic lipid interaction networks in female offspring, particularly altering glycerolipid and sterol lipid species. Mechanistically, O3 exposure activated key glycerolipid synthesis/catabolism genes (Mgll, Lpin1, Abhd6), upregulated cholesterol biosynthesis genes (Hmgcr, Hmgcs, Dhcr7, Sqle), and increased the mRNA expression of low-density lipoprotein cholesterol receptor (LDLR) and its regulatory protein PCSK9, collectively driving glycerolipid and cholesterol metabolic imbalance. Notably, transcription factor prediction analysis revealed a STAT3-centered regulatory network as the potential core molecular event mediating transgenerational metabolic effects of O3. This study uncovers that prenatal O3 exposure exerts long-lasting effects on hepatic metabolism in adult female offspring, providing novel mechanistic insights into how environmental pollutants may contribute to metabolic disorders.